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Research Square Jun 2024Lenalidomide maintenance is associated with a significantly improved progression-free in patients with newly diagnosed multiple myeloma. Maintenance with lenalidomide is...
Lenalidomide maintenance is associated with a significantly improved progression-free in patients with newly diagnosed multiple myeloma. Maintenance with lenalidomide is generally well tolerated; however, lenalidomide associated diarrhea is a common side effect and bile acid malabsorption has been suggested as an underlying mechanism. We conducted a single arm phase 2 trial of colesevelam, a bile acid binder, for lenalidomide-associated diarrhea in multiple myeloma. Patients were treated with colesevelam daily starting at 1250 mg (2 tablets 625 mg) for 12 weeks. The trial included 25 patients, 1 patient with grade 3 diarrhea, 14 with grade 2, and 10 with grade 1 diarrhea. All patients were on treatment with single agent lenalidomide maintenance and no patient progressed during the trial. Colesevelam treatment was highly effective for treatment of lenalidomide-associated diarrhea; 22 (88%) of the 25 patients responded where 17 patients (68%) had complete resolution of diarrhea, and 5 patients (20%) had improvement by 1 grade of diarrhea. The responses to colesevelam were seen within the first two weeks of treatment. These findings support the conclusion that lenalidomide-associated diarrhea is driven by bile acid malabsorption. Five patients reported mild gastrointestinal side effects including constipation. Importantly, the pharmacokinetics of lenalidomide were not affected by concomitant colesevelam treatment. The stool microbiome composition was not significantly different before and after colesevelam treatment. Patients reported improved diarrhea, fewer gastrointestinal symptoms, and less interference with their daily life after starting colesevelam. In summary, colesevelam was safe and highly effective for treatment of lenalidomide-associated diarrhea in multiple myeloma and does not reduce the clinical effect of lenalidomide.
PubMed: 38883739
DOI: 10.21203/rs.3.rs-4406606/v1 -
Mediterranean Journal of Hematology and... 2024
Impact of the Addition of Daratumumab to the Standard Bortezomib-Thalidomide-Dexamethasone Regimen on Hematopoietic Stem Cell Mobilization and Collection, Post-Transplant Engraftment and Infectious Complications: A Case-Control Multicentre Real-Life Analysis.
PubMed: 38882460
DOI: 10.4084/MJHID.2024.049 -
Mediterranean Journal of Hematology and... 2024
PubMed: 38882459
DOI: 10.4084/MJHID.2024.041 -
Mediterranean Journal of Hematology and... 2024The study of monoclonal serum proteins has led to the generation of two major theories: one proposing that individuals who had monoclonal proteins without any symptoms... (Review)
Review
The study of monoclonal serum proteins has led to the generation of two major theories: one proposing that individuals who had monoclonal proteins without any symptoms or evidence of end-organ damage have a benign condition, the other one suggesting that some individuals with asymptomatic monoclonal proteins may progress to multiple myeloma and thus are affected by a monoclonal gammopathy of undetermined significance (MGUS). Longitudinal studies of subjects with MGUS have supported the second theory. Subsequent studies have characterized and defined the existence of another precursor of multiple myeloma, smoldering multiple myeloma (SMM), intermediate between MGUS and multiple myeloma. Primary molecular events, chromosome translocations, and chromosome number alterations resulting in hyperploidy, required for multiple myeloma development, are already observed in myeloma precursors. MGUS and SMM are heterogeneous conditions with the presence of tumors with distinct pathogenic phenotypes and clinical outcomes. The identification of MGUS and SMM patients with a molecularly defined high risk of progression to MM offers the unique opportunity of early intervention with a therapeutic approach on a low tumor burden.
PubMed: 38882455
DOI: 10.4084/MJHID.2024.044 -
Ear, Nose, & Throat Journal Jun 2024Targeted therapies like denosumab have revolutionized multiple myeloma (MM) treatment, improved patient outcomes while introducing long-term complications. This study...
Targeted therapies like denosumab have revolutionized multiple myeloma (MM) treatment, improved patient outcomes while introducing long-term complications. This study explores a rare instance of delayed maxillary osteonecrosis post-denosumab therapy, delving into its pathophysiology and management. A 40-year-old male MM patient who developed a painful palatal lesion post denosumab treatment and diagnosed of maxillary osteonecrosis by computed tomography scan and surgical biopsy is presented. Treatment history, symptom progression, and response to the PENTOCLO protocol were analyzed. Post-denosumab discontinuation osteonecrosis highlights its prolonged impact on bone metabolism. PENTOCLO treatment protocol led to significant improvement. Genetic factors influencing osteonecrosis susceptibility have been discussed and considered. This case underscores the need for vigilance regarding long-term complications in MM survivors, preventive strategies, including regular dental evaluations and reducing invasive dental procedures, are crucial. We advocate for an interdisciplinary approach and further research into tailored prevention and management of osteonecrosis in cancer survivors.
PubMed: 38880987
DOI: 10.1177/01455613241263181 -
Nature Communications Jun 2024Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. It arises from mutational changes in immunoglobulin light chains. To...
Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. It arises from mutational changes in immunoglobulin light chains. To explore whether these mutations may affect the structure of the formed fibrils, we determine and compare the fibril structures from several patients with cardiac AL amyloidosis. All patients are affected by light chains that contain an IGLV3-19 gene segment, and the deposited fibrils differ by the mutations within this common germ line background. Using cryo-electron microscopy, we here find different fibril structures in each patient. These data establish that the mutations of amyloidogenic light chains contribute to defining the fibril architecture and hence the structure of the pathogenic agent.
Topics: Humans; Cryoelectron Microscopy; Immunoglobulin Light-chain Amyloidosis; Immunoglobulin Light Chains; Mutation; Amyloid; Male; Female; Middle Aged
PubMed: 38879609
DOI: 10.1038/s41467-024-49520-6 -
BMC Cancer Jun 2024Considering the age relevance of prostate cancer (PCa) and the involvement of the cGAS-STING pathway in aging and cancer, we aim to classify PCa into distinct molecular...
BACKGROUND
Considering the age relevance of prostate cancer (PCa) and the involvement of the cGAS-STING pathway in aging and cancer, we aim to classify PCa into distinct molecular subtypes and identify key genes from the novel perspective of the cGAS-STING pathway. It is of significance to guide personalized intervention of cancer-targeting therapy based on genetic evidence.
METHODS
The 430 patients with PCa from the TCGA database were included. We integrated 29 key genes involved in cGAS-STING pathway and analyzed differentially expressed genes and biochemical recurrence (BCR)-free survival-related genes. The assessments of tumor stemness and heterogeneity and tumor microenvironment (TME) were conducted to reveal potential mechanisms.
RESULTS
PCa patients were classified into two distinct subtypes using AURKB, TREX1, and STAT6, and subtype 1 had a worse prognosis than subtype 2 (HR: 21.19, p < 0.001). The findings were validated in the MSKCC2010 cohort. Among subtype 1 and subtype 2, the top ten mutation genes were MUC5B, DNAH9, SLC5A10, ZNF462, USP31, SIPA1L3, PLEC, HRAS, MYOM1, and ITGB6. Gene set variation analysis revealed a high enrichment of the E2F target in subtype 1, and gene set enrichment analysis showed significant enrichment of base excision repair, cell cycle, and DNA replication in subtype 1. TME evaluation indicated that subtype 1 had a significantly higher level of T cells follicular helper and a lower level of plasma cells than subtype 2.
CONCLUSIONS
The molecular subtypes mediated by the cGAS-STING pathway and the genetic risk score may aid in identifying potentially high-risk PCa patients who may benefit from pharmacologic therapies targeting the cGAS-STING pathway.
Topics: Humans; Male; Nucleotidyltransferases; Prostatic Neoplasms; Membrane Proteins; Signal Transduction; Prognosis; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Mutation; Aged; Gene Expression Profiling; Transcriptome
PubMed: 38877472
DOI: 10.1186/s12885-024-12492-3 -
Molecular Medicine (Cambridge, Mass.) Jun 2024Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly...
BACKGROUND
Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM.
METHODS
We first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells.
RESULTS
We found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN.
CONCLUSION
These results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse.
Topics: Multiple Myeloma; Humans; Animals; Neovascularization, Pathologic; HLA-G Antigens; Mice; Interleukin-6; Male; Female; Vascular Endothelial Growth Factor A; Middle Aged; Cell Line, Tumor; Hypoxia-Inducible Factor 1, alpha Subunit; Aged; Disease Models, Animal; Angiogenesis
PubMed: 38877399
DOI: 10.1186/s10020-024-00860-5 -
American Society of Clinical Oncology... Jun 2024Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in... (Review)
Review
Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in relapsed/refractory multiple myeloma (MM). Currently, these treatment share overlapping approval indications in the relapsed/refractory space, highlighting the importance of optimal selection and sequencing to maximize clinical efficacy. For patients previously unexposed to T-cell-directed therapies, several factors should be weighed when both options are available. These factors include access and logistical challenges associated with CAR T-cell therapy, disease-specific factors such as tempo of disease relapse, in addition to patient-specific factors such as frailty, and distinct toxicity profiles across these agents. Sequential therapy, whether it involves CAR T-cell therapy followed by bsAb or vice versa, has demonstrated clinical efficacy. When sequencing these agents, it is crucial to consider various factors that contribute to treatment resistance with careful selection of treatments for subsequent therapy in order to achieve favorable long-term patient outcomes.
Topics: Humans; Multiple Myeloma; Immunotherapy; Immunotherapy, Adoptive; Antibodies, Bispecific; Combined Modality Therapy; Treatment Outcome; Receptors, Chimeric Antigen
PubMed: 38875506
DOI: 10.1200/EDBK_432204 -
Medicine Jun 2024Pleural effusion, especially bilateral bloody pleural effusion, is a rare complication of Waldenström macroglobulinemia (WM). Pleural effusion in patients with WM has...
RATIONALE
Pleural effusion, especially bilateral bloody pleural effusion, is a rare complication of Waldenström macroglobulinemia (WM). Pleural effusion in patients with WM has many causes, such as infection, tumor invasion of the pleura, and rupture of the thoracic duct or its branches. Patients with WM presenting to the respiratory department with chest tightness and shortness of breath need more differential diagnosis by respiratory physicians, which is helpful for effective treatment. Herein, we present a case of MV diagnosis in a patient with bilateral bloody pleural effusion.
PATIENT CONCERN
Our patient is a 59-year-old man with WM presenting as having bilateral bloody pleural effusion.
INTERVENTIONS
The patient was treated with pleural effusion drainage. After confirming the diagnosis, the patient was treated with rituximab, cyclophosphamide, and dexamethasone.
OUTCOMES
Following these treatments, the patient's symptoms improved, and ultrasound showed a decrease in pleural effusion.
LESSONS
Despite its favorable prognosis, the cause of pleural effusion in a patient with WM can be challenging to diagnose. The cause of pleural effusion should be considered a differential diagnosis when diagnosing patients diagnosed with WM.
Topics: Humans; Waldenstrom Macroglobulinemia; Male; Middle Aged; Pleural Effusion; Diagnosis, Differential; Rituximab; Cyclophosphamide; Dexamethasone
PubMed: 38875392
DOI: 10.1097/MD.0000000000038406